Los Angeles SWAT officers Jack Traven and Harry Temple thwart an attempt by a bomber to hold an elevator full of people for a $3 million ransom. They corner the bomber, but he grabs Harry. Jack shoots Harry in the leg, forcing the bomber to release him. He turns and runs around a corner, apparently dying in an explosion. Jack and Harry are praised by their superior, Lieutenant "Mac" McMahon.

Wealthy Texan Big Enos Burdette (Pat McCormick) and his son Little Enos (Paul Williams) seek a truck driver willing to bootleg Coors beer to Georgia for their refreshment. At the time, Coors was regarded as one of the finest beers in the United States, but it could not be sold legally east of the Mississippi River. Truck drivers who had taken the bet previously had been caught and arrested by "Smokey" (CB slang for highway patrol officers, referring to the Smokey Bear–type hats worn in some states).

Big Enos Burdett (Pat McCormick) is running for Governor of Texas against another candidate, John Coen (David Huddleston). After a figurative and literal "mudslinging" between the two, they are both confronted by the outgoing governor and given a thorough tongue-lashing. As Burdett is leaving the office he overhears the governor yelling at an assistant to take responsibility for transporting a crate of unknown content from Miami to the Republican Party convention in Dallas. Burdett then schemes to pick up the crate and deliver it to the convention. He enlists the help of Bandit (Burt Reynolds) and Cledus (Jerry Reed) to carry out the task.

The film is presented in a nonlinear narrative, cutting back and forth between McCandless's time spent in Alaskan wilderness and his two-year travels leading up to his journey to Alaska. The plot summary here is told in a more chronological order.

While driving cross-country from Boston to San Diego in their new Jeep Grand Cherokee, Jeff Taylor and his wife Amy narrowly miss colliding with a beat-up Ford F-150 that darts in front of them from a connecting road on a deserted highway. Later, while stopped at a gas station, the truck's driver, Earl, exchanges hostile words with Jeff before the couple resume their journey. Shortly afterwards, their Jeep breaks down in the middle of the desert. Leaving Jeff with the car, Amy accepts a ride from a passing big rig trucker named Red Barr driving a Peterbilt 385, to get to a nearby diner and call for help. Jeff eventually discovers that the Jeep's battery connections have been suspiciously tampered with, and, after reconnecting them, drives to the diner, only to discover that no one has seen his wife. When he catches up to Barr on the road and forces him to stop, the trucker claims he has never seen Jeff or his wife before. Jeff hails a passing sheriff, named Boyd, but a brief search of Barr's truck yields no sign of Amy, and he is let go.

At the start of the summer holiday, Lewis Thomas (Paul Walker) and his childhood friend Venna Wilcox (Leelee Sobieski), who study at different universities, are both packing to go back home. In an attempt to get Venna romantically interested in him, Lewis offers to come by Venna's campus to drive her home instead of both of them flying back. Venna happily agrees and, after buying a car, Lewis starts his road-trip. When he calls his parents during the trip he learns his brother Fuller (Steve Zahn) has managed to once again get arrested, this time in Salt Lake City. Since Salt Lake City is not that far, Lewis decides that, prior to picking up Venna, he will visit Fuller, whom he hasn't seen in five years. After bailing him out, Fuller decides to accompany Lewis on his trip and, during the ride, coaxes Lewis into playing a cruel prank through their CB Radio on a truck driver, known only as 'Rusty Nail' (voiced by Ted Levine (uncredited)). Lewis pretends to be an attractive young woman named Candy Cane and sets up a meeting with Rusty Nail in the motel where Lewis and Fuller will be spending the night. But instead of giving Rusty his own room number, Lewis gives him the number of the room next door, which belongs to a highly irritable businessman who had an argument with Fuller earlier that night. When the joke takes a deadly turn, Lewis and Fuller find themselves being relentlessly stalked by the psychotic Rusty Nail. Needing gas, Lewis and Fuller stop at a gas station but are shocked when an ice truck follows them into the gas station. Convinced the truck driver must be Rusty Nail, Lewis and Fuller flee in panic only to discover they are being chased by the ice truck driver. However, it turns out the truck driver is merely trying to return Lewis' credit card which he left behind at the gas station. As the ice truck drives away, the real Rusty Nail in his truck ploughs through the ice truck, killing the innocent truck driver. He then proceeds to run over and crush the Lewis and Fuller's car, taunting them. Once the two apologize, Rusty accepts, and leaves.

Sam Hummer was a local truck driver from Tucson, Arizona who worked for a Tucson-based produce-shipper called "Red River". His driving partners were Duane Haller and "Pops" Dinwiddie. Eventually Sam's son, Carrol Jo, is old enough to ride with his father and the two of them then become partners as well. Sam changes the lettering on the trailer of his rig to read "Sam Hummer and Son".

Jimmy Hoffa and Bobby Ciaro are impatiently waiting in the parking lot of a roadhouse diner on July 30,1975. Others are late for a meeting. Asked if he wants to leave, Hoffa gives Ciaro a scornful glance. The first flashback to 1935 then occurs:

In the Arizona desert, truck driver Martin "Rubber Duck" Penwald is passed by a woman in a Jaguar E-Type, which leads to an encounter with a sheriff's deputy. Proceeding on his way, Rubber Duck runs into fellow truck drivers Pig Pen/Love Machine and Spider Mike, when another "trucker" informs them over the C.B. that they are okay to increase their speed. The "trucker" turns out to be cold county Sheriff "Dirty Lyle" Wallace, a long-time nemesis of the Duck, who extorts them for $70 each.

Lincoln Hawk is a struggling trucker who arm wrestles on the side to make extra cash while trying to rebuild his life. Hawk's estranged wife Christina, who is very ill, asks that Hawk pick up their son Michael from military school so that the two of them can get to know each other; Hawk had left them ten years earlier. Michael's controlling grandfather Jason Cutler, a wealthy man who hates Hawk and disapproved of his daughter's relationship with him, believes that Hawk has no right to be in his grandson's life. Michael is very distrusting and bitter towards Hawk initially and treats him with contempt at every turn.

The film tells the story of Simon Calmat (Vincent Lindon), a French swimming coach who is divorcing his wife Marion (Audrey Dana). Simon tries to help a young Iraqi-Kurd immigrant, Bilal Kayani (Firat Ayverdi), whose dream is to cross the English Channel from Calais in France to the United Kingdom by any means possible to be reunited with his girlfriend Mina (Derya Ayverdi). Meanwhile, Mina's father strongly opposes Bilal's plans as he wants to marry his daughter to her cousin who owns a restaurant. After being caught with other immigrants and returned to France, Simon gives him temporary refuge at his home after the young Bilal, nicknamed "Bazda" (runner, for his athletic abilities and love of football and Manchester United in particular) registers for swimming lessons, intending to train to be able to swim across the Channel. After police search Simon's apartment, Bilal goes on a final attempt and drowns 800 meters from the English coast while hiding from the coastguard. Simon then travels to inform Mina.

Truck driver Jack Burton (Kurt Russell) and his friend, restaurant owner Wang Chi (Dennis Dun), go to the airport to pick up Wang's fiancée Miao Yin (Suzee Pai), who is arriving from China. A Chinese street gang, the Lords of Death, tries to kidnap another Chinese girl at the airport who is being met by her friend Gracie Law (Kim Cattrall), intending to sell her as a sex slave. After Jack intervenes, they take Miao Yin instead. In Jack's big-rig truck, he and Wang track the Lords of Death to the back alleys of Chinatown, where they find a funeral procession that quickly erupts into a street fight between the Chang Sing and Wing Kong, two ancient Chinese societies. When "The Three Storms" (Thunder, Rain, and Lightning) appear, slaughtering the Chang Sing, Jack tries to escape but runs over Lo Pan (James Hong), a powerful and legendary sorcerer, as well as the leader of the Wing Kong. Horrified, Jack exits his truck, only to find Lo Pan, who is merely annoyed. Wang hurriedly guides Jack through the alleys, escaping the carnage and mayhem, but Jack's truck is stolen.

As the Earth passes through the tail of a comet, previously inanimate objects (ranging from weapons to electric signs to electronics to vehicles to lawnmowers to an electric knife) start to show a murderous life of their own. In a pre-title scene, a man (King in a cameo) tries to withdraw money from an ATM, but it instead calls him an "asshole", and he whines to his wife (King's real life wife Tabitha). Chaos soon begins as machines of all kinds come to life and begin assaulting humans: a drawbridge inexplicably raises during heavy traffic, resulting in multiple accidents, most notably the black AC/DC van and a watermelon truck; while at a Little League game, a vending machine kills the coach by firing canned soda point-blank into his groin and then to his skull; a driverless steamroller flattens one of the fleeing children.

As is the case with the two preceding Smokey and the Bandit films, Smokey and the Bandit Part 3 begins with Big Enos (Pat McCormick) and Little Enos (Paul Williams) offering a sizable wager on one's ability to transport a shipment a large distance in a short period of time. Offering a slight twist, however, the offer is this time made to a retiring Sheriff Buford T. Justice (Jackie Gleason), betting $250,000 against his badge on his ability to transport a large stuffed fish from an eatery in Florida to Texas.